This application addresses the broad Challenge area (06) Enabling Technologies, and the specific Challenge Topic, 06-EB-109: Model-Driven Biomedical Technology Development. Structural models of musculoskeletal tissues to calculate internal stresses and strains are an essential technology to investigate mechanisms of injuries and failure. Moreover accurate models provide understanding to predict the consequence of surgical interventions, device implantation, and tissue engineering. This proposal addresses the challenge of modeling the intervertebral disc. For over three decades finite element models have proved valuable to study disc mechanics. However, the currently available disc models have three significant limitations that will be addressed in this proposal for improved fidelity to predict mechanical behavior. First, the measured annulus fibrosus (AF) properties that are input into models are based on excised tissue tests. Excising the tissue disrupts the fiber structure, which introduces artifacts into the material property measurement and does not represent the inhomogeneities that are reflected by the gradual alterations in disc composition and microarchitecture. Second, excising tissue samples eliminates the interfaces between the sub-structures. Third, current disc models use "cable" elements that are embedded within an isotropic solid element for the AF. Ostensibly this represents the AF structure;however, the AF composition and microarchitecture is complex, requiring a constitutive formulation that better reflects the AF anisotropy, nonlinearity, and inhomogeneity. The objective of this proposal is to develop an image-based disc model that incorporates the tissue's inhomogeneous, anisotropic, and nonlinear material properties. We will obtain a 3D structural model with spatially distributed material properties using sophisticated enabling technologies. Aim 1: Extend the established 2D MRI to high resolution 3D MRI of the disc under load. Evaluate the performance of the pulse sequence and adjust the sequence parameters as required to optimize resolution, contrast, and signal-to-noise ratio. Aim 2: Image human discs under multi-axial loading configurations including compression, bending, and torsion and calculate 3D strain maps using state-of-the-art diffeomorphic image registration. Aim 3: Apply inverse methods to the established constitutive formulation and the measured strain maps to determine material properties. Validate the model and material properties by predicting strain under loading configuration not used in property calculations. Repeat the computational study using different loading modes for parameter regression. At completion of this study, we will be able to accurately predict the stresses and strains within the disc due to the microstructural contribution of the fibrillar components and extrafibrillar matrix and in response to interactions between the disc substructures. Determining material properties in situ is an innovative solution to the current limitations of artifacts in excised tissue tests and the disruption of sub-structural interfaces. The significance of this work lies in the development of an invaluable tool for accurate modeling of disc mechanics, which is central to both understanding mechanical failure of the disc and treating it. This system will initially be applied to cadaveric human tissues;however, long term advances in imaging may permit extension to in vivo application and patient-specific modeling and analysis. Economic impact The proposed experiments described in this Challenge Proposal will create four full time positions between the sites at the University of Pennsylvania (2.5 postdoctoral researchers, 0.2 technicians) and University of Minnesota (1 graduate student, 0.5 postdoctoral researchers). The University of Pennsylvania School of Medicine is an internationally recognized leader in the creation of new knowledge and therapies to improve human health, and in the training of the next generation of scientific leaders. In pursuit of these goals, the UPenn School of Medicine extends its economic impact widely and deeply throughout Pennsylvania, New Jersey, and Delaware. Recent studies attributed 37,000 jobs and $5.4 billion in economic activity to Penn Medicine in 2008. As Minnesota's only research university, the University of Minnesota is the economic engine for the state. As such the University of Minnesota's impact is felt far and wide, with more than 21,500 jobs directly related to research grants awarded to the University. This application addresses the broad Challenge area (06) Enabling Technologies, and the specific Challenge Topic, 06-EB-109: Model-Driven Biomedical Technology Development. Structural models that calculate the disc internal stresses and strains are essential to investigate mechanisms of disc injuries, tears, and failure. Moreover accurate models will provide understanding to predict the consequence of surgical interventions, device implantation, and tissue engineering. Unfortunately, the currently available disc models lack the fidelity to predict mechanical behavior accurately. The objective of this proposal is to develop an image-based disc model that incorporates the tissue's inhomogeneous, anisotropic, and nonlinear material properties. The proposed experiments described in this Challenge Proposal will create four full time positions between the sites at the University of Pennsylvania (2.5 postdoctoral researchers, 0.2 technicians) and University of Minnesota (1 graduate student, 0.5 postdoctoral researchers).